"A PROCESS FOR PREPARATION OF LEVOBUPIVACAINE"

Abstract

The present invention relates to a novel process for synthesis of a drug, levobupivacaine used as an anesthetic, by catalytic asymmetric synthesis of levobupivacaine to obtain a chiral intermediate which is converted into final product.

Full Text

Field of Invention:
This Invention relates to a novel process for preparation of levobupivacalne. The said drug is used as an anesthetic. More specifically, the invention relates to preparation of levobupivacalne from easily available raw materials (synthons) by catalytic asymmetric synthesis.
Backgound of the invention:
Buplvacalne and levobupivacalne (S-enantiomer of bupivacalne) are two widely used local anaesthetics. However, levobupivacalne is preferred on account of lower side-effects and better safety profile. Levobupivacalne is also called "1-butyl-N-(2,6-dlmethylphenyl)-2S-plperidinecarboxamide" and is referred to as such throughout the description.
R-(+)-bupivacalne is 3-4 times more likely to cause cardiovascular toxicity than S-(-)-buplvacalne in rabbit heatrts (Mazoit, J. X et al Anesth. Analg., 77: 477, 1993) and can also result in fatal cardiotoxicity if given intravenously by mistake or if used in excessive dose by other routes. (Kopacz et cd Anesth. Analg., 89: 1027, 1999). In contrast, levobupivacalne retains the anesthetic activity of the racemate and also produces less side-effects related to central nervous system. It has wider application as it has FDA approval for postoperative pain management as well (Grsitwood, R. et cd J. Exp. Opin. Invest. Drugs, 3: 1209, 1994).
Thus, levobupivacalne has considerable commercial Importance. Various methods for synthesis of levobupivacalne in the art are as described hereunder:
TuUar et cd (J. Med. Chem. 14(9): 891-2 (1971)/ Patent GB-A-1180712), describe a method using natural {R,R)-tartanc acid as the resolving agent for the separation of levobupivacalne and its antipode. One limitation of this method is that this is unsuited for preparation of levobupivacalne on an industrial scale, (R)-buplvacalne (R, JR)-tartrate salt crystallizes first, necessitating additional processing and therefore lowering the overall operating
efficiency besides increasing total time of product manufacture and enhanced costs.
Mannochio et al (WOO 176599) describes a process in which (R,R)-tartaric acid is used for the separation of levobupivacaine by preferential crystallization in which the unwanted {R,R)-tartrate-R-bupivacaine crystallizes first followed by the preferential crystallization of the S-bupivacaine (R,R)-tartrate. The disadvantage of this process is that it involves a number of crystallization steps at each stage which complicates the operation of purification of the desired final product.
Similar method using (R,R)-tartaric acid for resolution has also been reported by Marianne et al (US5994548) and Russo et al (US2004024021).
Method disclosed by Federsel et al, (Acta. Chem. Scand. B41:757, 1987), involves the use of 0.52 equivalents of a resolving agent dibenzoyl tartrate. The cost of this resolving agent being very high poses a serious limitation in extensive use of this method at a commercial scale.
Patent WO 96/12699 suggests the use of (S,S)-tartaric acid, precipitating directly the salt containing the levo-enantiomer by a procedure involving high temperatures. However, the resolving agent also known as unnatural tartaric acid, is ten to twenty times more expensive than natural tartaric acid, elevating considerably production cost of the product.
Hutton (US5929242, ZA9508497) describes the use of protected L-lysine for the synthesis of levobupivacaine, which suffers from several disadvantages like poor yield and use of costly protective groups.
Zavareh et al. (US5777124) describe the use of racemic, (R,S)-pipecolic acid for the synthesis of levobupivacaine, which is not advantageous as it requires use of resolving agents.
Dyer et al (W09628426) and Lock (W09611185) describe the use of chiral pipecolic acid for the synthesis of levobuplvaclne. (S)-plpecolic acid is obtained by the resolution of pipecolic acid with (S,S)tartaric acid in butyric acid, which is more costly than (R,R)-tartaric acid. Thus, the process also suffers from same limitation as other processes viz. use of expensive resolving agent.
Thus, all known processes as described above suffer from one limitation or the other. Broadly, the major limitations pertain to use of expensive resolving agents and also recycling of the unwanted Isomer which may vary from 50-60% of the product yield.
Thus, there is a need in the art to improve the process of preparation of levobupivacaine and provide a simple, cost-effective and economical process which does not suffer from the disadvantages and limitations present in the prior art. Accordingly, the present invention provides a process whereby levobupivacaine Is produced via asymmetric route and wherein use of expensive resolving agents Is avoided.
Objectives of the invention:
The main objective of the present invention is to provide a process for preparation of levobupivacaine by catalytic asymmetric synthesls route. Another objective is to provide a process, which does not use expensive resolving agents.
Statement of invention:
Accordingly, the invention provides a process for preparation of
levobupivacaine comprising the steps of:
I) Preparing N-(R)-2, 6-dimethyl aniline glyclnamide of formula 1
(Formula Removed)
wherein R is selected from H, benzyl and substituted benzyl such as 2-methoxy benzyl, 3,4-dimethoxy benzyl; by treating chloroacetyl chloride with N-R-2, 6-dimethyl aniline; 11) reacting the glyclnamide compound of formula (1) with 1 to 3 equivalents of an alkylating agent such as hereindescribed in the presence of a catalyst, a solvent and a base as hereindescribed, to obtain an alkylated compound of formula (2);
ill) cyclising compound of formula (2) by treating it with a reducing agent such as hereindescribed in the presence of a polar solvent such as hereindescribed and an inorganic base such as hereindescribed to obtain a compound of formula (3);
(Formula Removed)
Iv) treating compound of formula (3)
with palladium based catalyst under hydrogen atmosphere or with para-toluene sulphonic acid under reflux conditions in suitable solvent to obtain a deprotected picollnamide compound of formula (4), and
(Formula Removed)
v) treating compound of formula (4) with a alkylating agent to such as butyl bromide In the presence of potassium carbonate obtain levobuplvacalne or other analogues of the same like roplvacalne. Detailed description:
The present Invention provides a novel method of producing levobuplvacalne from easily available synthons. The staring material viz. benzophenone imine of N-(R)-2,6-dlmethyl aniline glyclnamlde 1 is easily prepared starting from chloroacetyl chloride and N-(R)-2,6-dimethylanillne (where R may be H, ben2yl, a substituted benzyl such as 2-methoxy benzyl, 3,4-dimethoxy benzyl). The preparation of compound 1 is as shown below (Scheme 1).
(Scheme Removed)
Once compound 1 is obtained, it is subject to catalytic asymmetric alkylation, using an alkylating agent in the presence of 0.1 mol% to 1 mol% of a chlral catalyst such as [(R,R)-3,4,5-trlfluorophenyl-NAS bromide] in a solvent and a base to yield an alkylated compound of formula 2 as shown in Scheme 2.
(Scheme Removed)
In the above scheme, the alkylating agent is l-chloro-4-iodobutane. The amount of alkylating agent is 1 to 3 equivalents with respect to compound of formula 1. The solvent is selected from methylene chloride or toluene or a mixture of both in various proportions. The said solvent is added to obtain a reaction concentration ranging from 0.23molar to 0.6 molar with respect to compound of formula 1. The base used is selected from KOH, NaOH, K2CO3 or CSOH.H2O either alone or as a mixture, preferably, mixture of CSOH.H2O and K2CO3 in a ratio of 2:10. The amount of base used may be 10 to 12 equivalents with respect to compound of formula 1. Preferably, the step of alkylation may be effected at a low temperature ranging from 0oC to -70°C. The optimal temperature for alkylation is -40°C and the step may be run for period ranging from 10 to 22 h.
The chiral catalyst used is in the ratio of 0.1 to 1 mol% (w.r.t compound 1); the best result being obtained using 0.10 mole percent of the catalyst.
The next step is the transformation of chiral alkylated compound 2 to obtain a cyclized compound 3 in an one-pot step by first reducing compound 2 using a mild reducing agent such as NaCNBH3, NaBH4 or any other milder boronic agent and then subjecting it to cyclization to obtain compound of formula 4. The solvent used for the reduction step is a mildly polar to polar solvent such as tetrahydrofuran, methanol, ethanol or any other ethereal or alcoholic solvent. The amount of solvent used is 0.07 molar to 0.5 molar with respect to compound of formula 2.
Compound 2 after the step of reduction, is treated with an inorganic base selected from K2CO3, Na2CO3, KOH, NaOH, and NaHCO3 to obtain a cyclized compound of formula 3. The amount of the inorganic base is l.5equivalents with respect to compound of formula 2.
The next step is deprotection of the amine and amide protecting groups present on compound 3 by treating compound 3 with a debenzylating agent such as
Pd/C or PdCl2 catalyst under hydrogen atmosphere or under refluxing condition using para toluene sulphonic acid to obtain a deprotected pipecolinamide compound of formula 4 in a single step. Primarily, this step involves debenzylation of amine and amide protecting groups using acetic acid or a mixture of ethyl acetate and acetic acid. A combination of EtOAc/AcOH in the ratio 4:1 is preferred. The amount of catalyst used may be 10 to 20mol% with respect to compound of formula 3.
The compound of formula 4 so obtained is subsequently converted into levobupivacaine by conventional method; by reacting compound of formula 4 with alkyl bromide like butyl bromide in dimethyl formamide in the presence of potassium carbonate.
The invention is now illustrated by the following examples, which are meant only to illustrate certain embodiments of the invention and should not be construed as limitations on the inventive scope thereof.
Example 1
Preparation of N1 -benzyl-N 1 -(2,6-dimethylphenyl)-2-diphenylmethyleneamino acetamide (i.e compound of formula 1)
To a stirred solution of N-benzyl-2,6-dimethylaniline (40 g) in toluene (150 mL) at 0 °C was added chloroacetyl chloride (12.8 g) drop wise over a period of 15 minutes. After stirring the suspension for 3 h at 30 °C, reaction mixture was filtered. Solvent was evaporated in vacuo and the residue dissolved in 1,4-dioxane (80 mL). Ammonia was bubbled through the solution kept at -10 °C for 30 min. and the resulting mixture was stirred at rt. for 3 h. 1,4-Dioxane was removed under vacuo and the residue dissolved in diethyl ether and filtered. The lilterate was acidified by bubbling HCl gas for 15 min., the precipated amine hydrochloride was filtered, dissolved in dry dichloromethane and was stirred with diphenyl methyl imine (16.0 g, 88.28 mmol) for 24 h. The suspension was filtered and the filterate was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was recrystallized from
ethyl acetate :hexane to afford 1 (Nl-benzyl-N1-(2,6-dimethylphenyl)-2-diphenylmethyleneaminoacetamide) as pale yellow crystalline solid (33.9 g, 83%). The aqueous layer was basified with 10% aqueous sodium hydroxide to recover the unreacted iV-benzyl-2,6-dimethylaniline. Mp 119 oC. IR (KBr): 3061, 3027, 2929, 1651, 1598, 1446, 1317, 1277, 1197, 1079, 1028, 919, 700. 1H NMR 5 (CDCl3, 300 MHz): 1.72 (s, 6H), 3.78 (s, 2H), 4.73 (s, 2H), 6.94 (d, J = 7.44, 2H), 7.02-7.37 (m, 14H), 7.61 (d, J= 7.14, 2H). MS (APCI): m/z 433 (M+ + 1, 100).
Example 2
(Nl-(2,6-dimethyphenyl)-Nl-(2-methoxybenzyl)-2-diphenylmethyleneamino acetamide) was synthesized according to the procedure given in Example 1 to obtain the product with 79% yield.
Example 3
(Nl-(2,4-dimethoxybenzyl)-Nl-(2,6-dimethyphenyl)-2-diphenylmethyleneamino acetamide) was synthesized according to the procedure given in Example 1 to obtain the product with 82% yield.
Example 4
Nl-benzyl-Nl-(2,6-dimethylphenyl)-(2S)-6-chloro-2-diphenylmethyleneaminohexanamide (i.e compound of formula 2) Under argon, to a cooled (-40 °C) and stirred solution of 1 (0.500 g, 1.15 mmol), (R,R)-3,4,5-trifluorophenyl-NAS bromide (10.5 mg, 0.011 mmol), CsOH.H2O (0.388 g, 2.31 mmol) and potassium carbonate (1.59 g, 11.5 mmol) in toluene (5 mL) was added l-chloro-4-iodobutane (0.75 g, 3.46 mmol) via a syringe pump. The contents were stirred magnetically for 22 h. The reaction mixture was diluted with Et2O (20 mL) and the contents were filtered. The filtrate was
washed with water (10 mL), brine (10 mL), dried over dried over Na2SO4 and
concentrated in vacuo, the residue was passed through a short pad of silica to
afford 2 (Nl-benzyl-Nl-(2,6-dimethylphenyl)-(2S)-6-chloro-2-
diphenylmethyleneaminohexanamide.) as an oil (0.513 g, 85%).
Enantioselectivity was determined by chiral HPLC analysis [α]D25= 56.53 (c 0.5, CHCl3), ee 96%. IR (KBr): 3053, 2958, 2932, 2854, 1655, 1444, 1400, 1312, 1286, 1254, 1233, 1188, 1079, 772. 1H NMR 5 (CDCl3, 300 MHz): 1.02-1.07 (m, 2H), 1.31 (m, 1H), 1.49 (s, 3H), 1.48 (m, 2H), 1.92 (s, 3H), 2.3 (m, 1H), 3.34 (t, J= 6.61, 2H), 3.64 (dd, J= 2.79, 7.02, 1H), 4.22 (d, J= 13.49, 1H), 5.34 (d, J= 13.49, 1H), 6.18 (d, J= 6.93, 2H), 6.98 (t, J= 6.69, 2H), 7.12-7.55 (m, 14H). MS (APCI): m/z 525 (M+ +2, 42), 523 (100).
Example 5
The above procedure as in Example 4 when performed using toluene:dichloromethane (7:3) the product was obtained with 85%ee and 73% yield after 22 h.
Example 6
The above procedure as in Example 4 when performed using toluene at -20 °C, the product was obtained with 76 % yield after 15 h.
Example 7
The above procedure as in Example 4 when performed using toluene at -70 "C, the product was obtained with 96% ee and 78 % yield after 30 h.
Example 8
The above procedure as in Example 4 when performed using KOH as base, the reaction did not proceed.
Examiple 9
The above procedure as in Example 4 when performed using CSOH.H2O as base, the product was obtained with 96%ee and 54% yield after 20 h.
Example 10
The above procedure as in Example 4 when performed using K2CO3 as base, the reaction did not proceed.
Example 11
The above procedure as in Example 4 when performed using toluene at -40 °C,
with N1 -(2,6-dimethyphenyl)-N 1 -(2-methoxybenzyl) -2-
diphenylmethyleneaminoacetamide, the product (Nl-(2,6-dimethylphenyl)-Nl-(2-methoxybenzyl-(2S)-6-chloro-2-diphenylmethyleneaminohexanamide) was obtained with 95% ee and 79% yield after 22 h.
Example 12
The above procedure as in Example 4 when performed using toluene at -40 °C, with N1 -(2,4-dimethoxybenzyl)-N 1 -(2,6-dimethyphenyl)-2-
diphenylmethyleneaminoacetamide the product (Nl-(2,4-dimethoxybenzyl-Nl-(2,6-dimethylphenyl)-(2S)-6-chloro-2-diphenylmethyleneaminohexanamide) was obtained with 95.5% ee and 81% yield after 22 h.
Example 13
N2-benzyl-N2-(2,6-dimethylphenyl)-(2S)-l-benzhydrylhexahydro-2-pyridinecarboxamide (i.e compound of formula 3)
To an ice cooled (0 °C) solution of 2 (0.350 g, 0.66 mmol) in THF (5 mL) was added sodium cyanoborohydride (0.084 g, 1.32 mmol). After stirrinig the reaction mixture for 35 min., NaHCO3 and Nal (20 mg) was added to the reaction mixture and the contents were stirred at 80 0C for 8 h. Solvent was removed in vacuo and the residue dissolved in CH2Cl2, washed with water,
brine, dried over anhydrous Na2SO4 and concentrated to afford 3 (N2-benzyI-N2-(2,6-dimethylphenyl)-(2S)-l-benzhydrylhexahydro-2-pyridinecarboxamide). as white solid (92%). Mp 62 0C, [α]25D= +62.14 (c 0.2, CHCl3). IR (KBr): 3060, 3027, 2930, 2856, 1647, 1490, 1450, 1376, 1237, 1192, 1121, 1076, 972, 743. 1H NMR (CDCl3): 0.74 (s, 3H), 1.31-1.73 (m, 6H), 2.01 (s, 3H), 2.56 (d, J = 11.861H), 3.40 (m, 2H), 3.95 (d, J =13.48, 1H), 5.36 (s, 1H), 5.39 (d, J = 13.68, 1H), 7.01-7.28 (m, 14H), 7.35 (d, J = 7.61 , 2H), 7.44 (d, J = 7.69 , 1H), 7.54 (d, J = 7.20, 1H). MS (APCI): m/z 489 (M++1, 45), 167 (100).
Example 14
The above procedure as in Example 13 when performed using sodium borohydride the product was obtained with 5% yield after 1 h.
Example 15
To a solution of 3 (0.100 g) in a mixture of EtOAc/AcOH (4:1, 5 mL) was added PdCl2 (6 mg) and the resulting suspension hydrogenated on a Parr hydrogenator at 40 psig for 6 h. The solvent was removed and the residue was dissolved in CH2Cl2, basified with aq. Na2CO3, dried over anhydrous Na2SO4 and concentrated to afford 4 as white solid (95%). IR (KBr): 3321, 3254, 3025, 2929, 2851, 1655, 1623, 1530, 1450, 1309, 1225, 1124, 763. MS (MALDl): 232 (M+).
Example 16
The above procedure as in Example 15 when performed using only acetic acid the product was obtained with 85% yield after 6 h.
Example 17
The above procedure as in Example 15 when performed using only ethyl acetate the product was obtained with 10% yield after 6 h.
Example 18
Preparation of levobupivacaine from N-(2,6-dimethylphenyl)-(2S)-2-pyridinecarboxamide as given in prior art; by reacting compound of formula 4 with alkyl bromide like butyl bromide in dimethyl formamide in the presence of potassium carbonate .
The final product is obtained in high yield and enantiomeric excess by the process of the present invention which is comparable to that reported in the prior art.
Advantages:
The process of present invention has the following advantages over the prior art:-
1. Requirement of costly resolving agents is eliminated.
2. The need for recycling of unwanted isomer is eliminated.
3. The process uses readily available, simple, achiral synthons as starting material.
4. The catalytic asymmetric alkylation process creates a new chiral center using synthons such as protected glycinamide.
5. The invention achieves high chemical yield of final product levobupivacaine i.e. to the extent of 65 percent of overall yield and the final product is obtained in enantiomeric excess of >98 percent.
6. The process involves fewer steps than prior art processes.
7. Chiral catalyst is used in very small quantity to obtain levobupivacaine of desired chirality.

We Claim:
1. A process for preparation of levobupivacaine comprising the steps of:
i) preparing N-(R)-2, 6-dimethylaniline glycinamide of formula
1 from chloroacetyl chloride and N-(R)-2, 6-dimethylaniline;
(Formula Removed)
wherein R is selected from H, benzyl and substituted benzyl such as 2-methoxy benzyl, 3,4-dimethoxy benzyl; by treating chloroacetyl chloride with N-(R)-2, 6-dimethyl aniline; ii) reacting compound of formula (1) with 1 to 3 equivalents of l-chloro-4-iodobutane with (R,R)-3,4,5-trifluorophenyl-NAS-bromide, a solvent and a base as hereindescribed, to obtain an alkylated compound of formula (2);
(Formula Removed)
iii) treating compound of formula (2) with a reducing agent such as hereindescribed in the presence of a polar solvent such as hereinde scribed at a tempearture in the range of 0 to -70°C and cyclising in the presence of an inorganic base such as hereindescribed to obtain a compound of formula (3);
(Formula Removed)
iv) treating compound of formula (3) with Pd/C or PdCl2 catalyst under hydrogen atmosphere or under refluxing condition using para toluene sulphonic acid to obtain a deprotected pipecolinamide compound of formula (4)
(Formula Removed)
v) treating compound of formula (4) with a alkylating agent such as butyl bromide in the presence of potassium carbonate to obtain levobupivacaine.
2. A process as claimed in claim 1 wherein the solvent is methylene chloride or toluene or a mixture thereof and is added to obtain a reaction mixture of concentration ranging from 0.23 Molar to 0.6 Molar with respect to compound of formula 1.
3. A process as claimed in claim 1 wherein the base in step (ii) is selected from potassium hydroxide, sodium hydroxide, potassium carbonate, cesium hydroxide or a mixture thereof.
4. A process as claimed in claim 5 wherein the amount of base is 10 to 12 equivalents with respect to compound of formula 1.
5. A process as claimed in claim 1 wherein the base is a mixture of CSOH.H2O and K2CO3 in a ratio of 2:10.
6. A process as claimed in claim 1 wherein step (ii) is run at -400C for 22 hours.
7. A process as claimed in claim 1 wherein the amount of catalyst in step (ii) is 0.1 to 1 mol% of the compound of formula 1.
8. A process as claimed in claim 1 wherein the reducing agent is selected from NaCNBH3, NaBH4 or a boronic agent.
9. A process as claimed in claim 1 wherein the polar solvent is selected from tetrahydrofuran, methanol and ethanol.
10. A process as claimed in claim 15 wherein the polar solvent is added to obtain a reaction mixture of concentration ranging from 0.07 Molar to 0.5 Molar with respect to compound of formula 2.
11. A process as claimed in claim 1 wherein the amount of reducing agent is 2 equivalents with respect to compound of formula 2.
12. A process as claimed in claim 1 wherein the inorganic base is selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and sodium bicarbonate and the amount of inorganic base is 1.5 equivalents with respect to compound of formula 2.
13. A process as claimed in claim 1 wherein the amount of catalyst is 10 to 20 mol% with respect to the compound of formula 3.
14. A process as claimed in claim 1 wherein the solvent in step (ii) is ethyl acetate-acetic acid in a ratio of 4:1.
15. A process for preparing levobupivacaine substantially as hereindescribed and illustrated with reference to the examples.